Treatment for obesity

ABSTRACT

The present invention relates to a method for treating or preventing obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds. The invention further relates to methods for reducing body weight and/or reducing food intake in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds.

STATEMENT OF PRIORITY

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 14/955,646, filed Dec. 1, 2015, which is acontinuation of and claims priority to U.S. patent application Ser. No.14/334,694, filed Jul. 18, 2014, now U.S. Pat. No. 9,226,910, whichclaims the benefit of U.S. Provisional Application Ser. No. 61/847,593,filed Jul. 18, 2013, the entire contents of each of which areincorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a method for treating or preventingobesity in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of certain carbamatecompounds. The invention further relates to methods for reducing bodyweight and/or reducing food intake in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of certain carbamate compounds.

BACKGROUND

Obesity is worldwide health problem that is reaching epidemicproportions. As of 2008 the World Health Organization estimates that atleast 500 million adults are obese. The United States has the highestrates of obesity in the developed world. It was reported in 2010 that35.7% of US adults are obese. Overweight and obesity are the fifthleading risk for global deaths.

Obesity is a complex disease influenced by genetics, diet, exercise, anda complex biology. Bariatric surgery to reduce the size of the stomach(gastric bypass surgery) is the only effective treatment for causingweight loss in morbidly obese people. Drugs to treat obesity can bedivided into three groups: those that reduce food intake or appetitesuppressants; those that alter metabolism or block the absorption offat; and those that increase thermogenesis. Currently, there are onlytwo drugs approved by the FDA for the long-term treatment of obesity:the fat absorption blocker orlistat (XENICAL®, ALLI®) and the appetitesuppressant sibutramine (MERIDIA®). These drugs cause serious sideeffects and only result in modest weight loss. Thus, discovery of novelobesity treatments is urgently needed.

SUMMARY OF EMBODIMENTS OF THE INVENTION

The present invention provides an effective and convenient method fortreatment or prevention of obesity and to help people reduce body weightand/or food intake. Thus, in one aspect the present invention isdirected to a method for treating obesity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integerof 0 to 3, with the proviso that R may be the same or different when xis 2 or 3; R₁ and R₂ are independently selected from the groupconsisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle that is unsubstituted or substituted withone or more alkyl or aryl groups, wherein the heterocycle can comprise 1to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atomsare not directly connected with each other or with the oxygen atom;wherein the subject reduces body weight, thereby treating the obesity.

In another aspect the present invention is directed to a method forreducing body weight in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integerof 0 to 3, with the proviso that R may be the same or different when xis 2 or 3; R₁ and R₂ are independently selected from the groupconsisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle that is unsubstituted or substituted withone or more alkyl or aryl groups, wherein the heterocycle can comprise 1to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atomsare not directly connected with each other or with the oxygen atom;wherein the subject reduces body weight.

In another aspect the present invention is directed to a method forreducing food intake in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integerof 0 to 3, with the proviso that R may be the same or different when xis 2 or 3; R₁ and R₂ are independently selected from the groupconsisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle that is unsubstituted or substituted withone or more alkyl or aryl groups, wherein the heterocycle can comprise 1to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atomsare not directly connected with each other or with the oxygen atom;wherein the subject reducing food intake.

In some embodiments of the invention the methods comprise the step ofadministering to the subject an effective amount of an enantiomer ofFormula I substantially free of other enantiomers or an enantiomericmixture wherein one enantiomer of Formula I predominates.

In some embodiments, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the compound of Formula I is a compound of FormulaIb:

or a pharmaceutically acceptable salt or ester thereof. This compound isnamed (R)-(beta-amino-benzenepropyl) carbamate orO-carbamoyl-(D)-phenylalaninol and has alternatively been calledADX-N05, SKL-N05, SK-N05, YKP10A, and R228060.

Embodiments of the invention include use of a compound of Formula I fortreating obesity in a subject in need thereof. Other embodiments of theinvention include use of a compound of Formula I for reducing bodyweight and/or food intake in a subject in need thereof.

Embodiments of the invention include the use, for the preparation of amedicament for the treatment of obesity, of a compound of Formula I.Other embodiments of the invention include use, for reducing body weightand/or food intake in a subject in need thereof, of a compound ofFormula I.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention now will be described hereinafter with referenceto the accompanying drawings and examples, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription of the invention herein is for the purpose of describingparticular embodiments only and is not intended to be limiting of theinvention.

Unless the context indicates otherwise, it is specifically intended thatthe various features of the invention described herein can be used inany combination. Moreover, the present invention also contemplates thatin some embodiments of the invention, any feature or combination offeatures set forth herein can be excluded or omitted. To illustrate, ifthe specification states that a composition comprises components A, Band C, it is specifically intended that any of A, B or C, or acombination thereof, can be omitted and disclaimed singularly or in anycombination.

Definitions

As used herein, “a,” “an,” or “the” can mean one or more than one. Forexample, “a” cell can mean a single cell or a multiplicity of cells.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

The term “about,” as used herein when referring to a measurable valuesuch as an amount of dose (e.g., an amount of a compound) and the like,is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even±0.1% of the specified amount.

The terms “comprise,” “comprises,” and “comprising” as used herein,specify the presence of the stated features, integers, steps,operations, elements, and/or components, but do not preclude thepresence or addition of one or more other features, integers, steps,operations, elements, components, and/or groups thereof.

As used herein, the transitional phrase “consisting essentially of”means that the scope of a claim is to be interpreted to encompass thespecified materials or steps recited in the claim “and those that do notmaterially affect the basic and novel characteristic(s)” of the claimedinvention. See, In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q. 461,463(CCPA 1976) (emphasis in the original); see also MPEP § 2111.03. Thus,the term “consisting essentially of” when used in a claim or thedescription of this invention is not intended to be interpreted to beequivalent to “comprising.”

As used herein, the terms “increase,” “increases,” “increased,”“increasing,” and similar terms indicate an elevation of at least about25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500% or more.

As used herein, the terms “reduce,” “reduces,” “reduced,” “reduction,”and similar terms mean a decrease of at least about 5%, 10%, 15%, 20%,25%, 35%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or more. In particularembodiments, the reduction results in no or essentially no (i.e., aninsignificant amount, e.g., less than about 10% or even 5%) detectableactivity or amount.

“Effective amount” as used herein refers to an amount of a compound,composition and/or formulation of the invention that is sufficient toproduce a desired effect, which can be a therapeutic and/or beneficialeffect. The effective amount will vary with the age, general conditionof the subject, the severity of the condition being treated, theparticular agent administered, the duration of the treatment, the natureof any concurrent treatment, the pharmaceutically acceptable carrierused, and like factors within the knowledge and expertise of thoseskilled in the art. As appropriate, an “effective amount” in anyindividual case can be determined by one of skill in the art byreference to the pertinent texts and literature and/or by using routineexperimentation.

By the term “treat,” “treating,” or “treatment of” (and grammaticalvariations thereof) it is meant that the severity of the subject'scondition is reduced, at least partially improved or ameliorated and/orthat some alleviation, mitigation or decrease in at least one clinicalsymptom is achieved and/or there is a delay in the progression of thedisease or disorder. With respect to obesity, the term refers to, e.g.,a decrease in body mass index, a decrease in body weight, and/or adecrease in body fat. In some embodiments, treatment provides areduction in body weigh by at least about 5%, e.g., about 10%, 15%, or20%.

A “therapeutically effective” amount as used herein is an amount that issufficient to treat (as defined herein) the subject. Those skilled inthe art will appreciate that the therapeutic effects need not becomplete or curative, as long as some benefit is provided to thesubject.

The terms “prevent,” “preventing,” and “prevention” (and grammaticalvariations thereof) refer to prevention and/or delay of the onset of adisease, disorder and/or a clinical symptom(s) in a subject and/or areduction in the severity of the onset of the disease, disorder and/orclinical symptom(s) relative to what would occur in the absence of themethods of the invention. The prevention can be complete, e.g., thetotal absence of the disease, disorder and/or clinical symptom(s). Theprevention can also be partial, such that the occurrence of the disease,disorder and/or clinical symptom(s) in the subject and/or the severityof onset is less than what would occur in the absence of the presentinvention. With respect to obesity, the term refers to, e.g., preventingobesity from occurring if the treatment is administered prior to theonset of the obese condition. In some embodiments, prevention refers toa decrease in the amount of body weight gained compared to the amount ofbody weight gained in the absence of administration of the compounds ofthe invention.

A “prevention effective” amount as used herein is an amount that issufficient to prevent and/or delay the onset of a disease, disorderand/or clinical symptoms in a subject and/or to reduce and/or delay theseverity of the onset of a disease, disorder and/or clinical symptoms ina subject relative to what would occur in the absence of the methods ofthe invention. Those skilled in the art will appreciate that the levelof prevention need not be complete, as long as some benefit is providedto the subject.

A “subject” of the invention includes any animal that has or issusceptible to obesity or is in need of reducing body weight, bodyweight gain, and/or food intake. Such a subject is generally a mammaliansubject (e.g., a laboratory animal such as a rat, mouse, guinea pig,rabbit, primate, etc.), a farm or commercial animal (e.g., a cow, horse,goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog,ferret, etc.). In particular embodiments, the subject is a primatesubject, a non-human primate subject (e.g., a chimpanzee, baboon,monkey, gorilla, etc.) or a human. Subjects include males and/or femalesof any age, including neonates, juveniles, adolescents, adults andgeriatric subjects.

A “subject in need” of the methods of the invention can be a subjectknown to have, suspected of having, or having an increased risk ofdeveloping overweight or obesity.

As used herein the term “body mass index” or “BMI” means the ratio ofweight in Kg divided by the height in meters, squared.

As used herein the term “overweight” refers to a BMI between 25 and 30in adult humans. For people under 20 “overweight” is defined as a BMIbetween the 85th and 95th percentile compared to people of the same age.

As used herein the term “obesity” refers to a BMI between 30 and 40 inadult humans. For people under 20 “obesity” is defined as a BMI abovethe 95th percentile compared to people of the same age. As used herein,the term can include both obesity and morbid obesity.

As used herein the term “morbid obesity” refers to a BMI greater than 40in adult humans.

As used herein the term “body weight” refers to the weight of asubject's body.

As used herein the term “body weight gain” refers to the increase inweight of a subject's body over time.

As used herein the term “food intake” refers to the intake of caloriesin any form, including without limitation food, drink, intravenous, orenteral.

The term “pharmaceutically acceptable salts or esters” shall meannon-toxic salts or esters of the compounds employed in this inventionwhich are generally prepared by reacting the free acid with a suitableorganic or inorganic base or the free base with a suitable organic orinorganic acid. Examples of such salts include, but are not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,oleate, oxalate, pamoate, palmitate, panthothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide, and valerate.

As used herein the term “concomitant administration” or “combinationadministration” of a compound, therapeutic agent or known drug with acompound of the present invention means administration of a knownmedication or drug and, in addition, the one or more compounds of theinvention at such time that both the known drug and the compound willhave a therapeutic effect. In some cases this therapeutic effect will besynergistic. Such concomitant administration can involve concurrent(i.e., at the same time), prior, or subsequent administration of theknown drug with respect to the administration of a compound of thepresent invention. A person of skill in the art, would have nodifficulty determining the appropriate timing, sequence and dosages ofadministration for particular drugs and compounds of the presentinvention.

In addition, in some embodiments, the compounds of this invention willbe used, either alone or in combination with each other or incombination with one or more other therapeutic medications as describedabove, or their salts or esters, for manufacturing a medicament for thepurpose of providing treatment for obesity to a patient or subject inneed thereof.

The present invention is based in part on the discovery thatphenylalkylamino carbamates of Formula I have novel and uniquepharmacological properties. Without being limited by mechanism, it isthought that the compounds of Formula I function in part by increasingdopamine levels. The neurotransmitter dopamine mediates the reward valueof food and it has been found that obese individuals have decreaseddopamine receptor D2 availability. Dopamine modulates motivation andreward circuits and hence dopamine deficiency in obese individuals mayperpetuate pathological eating as a means to compensate for decreasedactivation of these circuits. Thus, strategies aimed at improvingdopamine function may be beneficial in the treatment of obesity.Amphetamines and amphetamine-like drugs suppress appetite due tostimulation of dopamine signaling and have been used for decades asappetite suppressants to treat obesity; however their appetitesuppressant effects are linked to a high risk of addiction. Innonclinical studies in mice, rats, and dogs, administration of thecompound of Formula Ib is associated with decreases in body weightand/or body weight gain as well as reductions in food consumption. Thepresent compounds, however, show no clear abuse potential; the compoundof Formula Ib was not reinforcing in the classic rat self-administrationmodel and showed no significant rewarding properties in the placepreference model. In a 6-week clinical study in major depressivedisorder patients examining the antidepressant effects of the compoundof Formula Ib, the compound was associated with a dose-related decreasein weight relative to placebo treated patients. There was also anincrease in reporting of anorexia in the compound-treated groups. Forthese reasons the compounds of Formula I are especially suitable forreduction in body weight and treatment of obesity.

One aspect the present invention is directed to a method for treatingobesity in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integerof 0 to 3, with the proviso that R may be the same or different when xis 2 or 3; R₁ and R₂ are independently selected from the groupconsisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle that is unsubstituted or substituted withone or more alkyl or aryl groups, wherein the heterocycle can comprise 1to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atomsare not directly connected with each other or with the oxygen atom;wherein the subject reduces body weight, thereby treating the obesity.

In another aspect the present invention is directed to a method forreducing body weight or body weight gain in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integerof 0 to 3, with the proviso that R may be the same or different when xis 2 or 3; R₁ and R₂ are independently selected from the groupconsisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle that is unsubstituted or substituted withone or more alkyl or aryl groups, wherein the heterocycle can comprise 1to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atomsare not directly connected with each other or with the oxygen atom;wherein the subject reduces body weight.

In another aspect the present invention is directed to a method forreducing food intake in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R is amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy,trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integerof 0 to 3, with the proviso that R may be the same or different when xis 2 or 3; R₁ and R₂ are independently selected from the groupconsisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl,cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a5 to 7-membered heterocycle that is unsubstituted or substituted withone or more alkyl or aryl groups, wherein the heterocycle can comprise 1to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atomsare not directly connected with each other or with the oxygen atom;wherein the subject reducing food intake.

In some embodiments, the subject is obese or morbidly obese and is inneed of reducing weight or reducing/preventing further weight gain. Insome embodiments, the subject is overweight and is in need of reducingbody weight to the normal range and/or reducing/preventing furtherincrease in body weight or becoming obese. In some embodiments, thesubject is normal weight and wants to reducing/prevent an increase inbody weight.

In some embodiments of the above methods, R is a member selected fromthe group consisting of alkyl of 1 to 3 carbon atoms, halogen, alkoxy of1 to 3 carbon atoms, nitro, hydroxy, and trifluoromethyl. In someembodiments of the above methods, R is a member selected from the groupconsisting of alkyl of 1 to 3 carbon atoms, halogen, and alkoxy of 1 to3 carbon atoms.

In some embodiments of the above methods, R₁ and R₂ are independentlyselected from the group consisting of hydrogen, alkyl of 1 to 8 carbonatoms, aryl, arylalkyl, and cycloalkyl of 3 to 7 carbon atoms. In someembodiments of the above methods, R₁ and R₂ are independently selectedfrom the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms.In some embodiments of the above methods, R₁ and R₂ are independentlyselected from the group consisting of hydrogen and alkyl of 1 to 3carbon atoms.

It is understood that substituents and substitution patterns on thecompounds of the present invention can be selected by one of skill inthe art to provide compounds that are chemically stable and that can bereadily synthesized by techniques known in the art as well as themethods provided herein.

In one embodiment, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment the compound of Formula I is the (D) enantiomerwherein R₁ and R₂ are hydrogen and x is 0 (compound Ib).

or a pharmaceutically acceptable salt or ester thereof. This compound isthe (R) enantiomer, if named by structure and is therefore(R)-(beta-amino-benzenepropyl) carbamate. This compound is thedextrorotary enantiomer and can therefore also be namedO-carbamoyl-(D)-phenylalaninol. These names may be used interchangeablyin this specification.

The present invention includes the use of isolated enantiomers of thecompound of Formula I (e.g., compounds of Formula Ia or Ib). In oneembodiment, a pharmaceutical composition comprising the isolatedS-enantiomer of Formula I is used to provide treatment to a subject. Inanother embodiment, a pharmaceutical composition comprising the isolatedR-enantiomer of Formula I is used to provide treatment to a subject.

The present invention also includes the use of mixtures of enantiomersof Formula I. In one aspect of the present invention, one enantiomerwill predominate. An enantiomer that predominates in the mixture is onethat is present in the mixture in an amount greater than any of theother enantiomers present in the mixture, e.g., in an amount greaterthan 50%. In one aspect, one enantiomer will predominate to the extentof 90% or to the extent of 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% orgreater. In one embodiment, the enantiomer that predominates in acomposition comprising a compound of Formula I is the S-enantiomer ofFormula I.

The present invention provides methods of using enantiomers andenantiomeric mixtures of compounds represented by Formula I. A carbamateenantiomer of Formula I contains an asymmetric chiral carbon at thebenzylic position, which is the second aliphatic carbon adjacent to thephenyl ring.

An enantiomer that is isolated is one that is substantially free of thecorresponding enantiomer. Thus, an isolated enantiomer refers to acompound that is separated via separation techniques or prepared free ofthe corresponding enantiomer.

The term “substantially free,” as used herein, means that the compoundis made up of a significantly greater proportion of one enantiomer. Inpreferred embodiments, the compound includes at least about 90% byweight of one enantiomer. In other embodiments of the invention, thecompound includes at least about 99% by weight of one enantiomer.

The compounds of Formula I can be synthesized by methods known to theskilled artisan. The salts and esters of the compounds of Formula I canbe produced by treating the compound with a suitable mineral or organicacid (HX) in suitable solvent or by other means well known to those ofskill in the art.

Details of reaction schemes for synthesizing compounds of Formula I aswell as representative examples on the preparation of specific compoundshave been described in U.S. Pat. No. 5,705,640, U.S. Pat. No. 5,756,817,U.S. Pat. No. 5,955,499, U.S. Pat. No. 6,140,532, all incorporatedherein by reference in their entirety.

From Formula I it is evident that some of the compounds of the inventionhave at least one and possibly more asymmetric carbon atoms. It isintended that the present invention include within its scope thestereochemically pure isomeric forms of the compounds as well as theirracemates. Stereochemically pure isomeric forms may be obtained by theapplication of art known principles. Diastereoisomers may be separatedby physical separation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereoselectivereactions.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. GO. M. Wuts,Protective Groups in Organic Synthesis, Third Edition, John Wiley &Sons, 1999. The protecting groups may be removed at a convenientsubsequent stage using methods known in the art.

The compound may be administered to a subject by any conventional routeof administration, including, but not limited to, oral, buccal, topical,systemic (e.g., transdermal, intranasal, or by suppository), orparenteral (e.g., intramuscular, subcutaneous, or intravenousinjection.) Administration of the compounds directly to the nervoussystem can include, for example, administration to intracerebral,intraventricular, intracerebralventricular, intrathecal, intracisternal,intraspinal or peri-spinal routes of administration by delivery viaintracranial or intravertebral needles or catheters with or without pumpdevices. Depending on the route of administration, compounds of FormulaI can be constituted into any form. For example, forms suitable for oraladministration include solid forms, such as pills, gelcaps, tablets,caplets, capsules, granules, and powders (each including immediaterelease, timed release and sustained release formulations). Formssuitable for oral administration also include liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. In addition,forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

In certain embodiments, pharmaceutical compositions of this inventioncomprise one or more compounds of Formula I or a salt or ester thereofwithout any pharmaceutical carriers or excipients. In other embodiments,pharmaceutical compositions of this invention comprise one or morecompounds of formula I or a salt or ester thereof intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. Carriers are inert pharmaceutical excipients,including, but not limited to, binders, suspending agents, lubricants,flavorings, sweeteners, preservatives, dyes, and coatings. In preparingcompositions in oral dosage form, any of the usual pharmaceuticalcarriers may be employed. For example, for liquid oral preparations,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like.

Compositions can take the form of tablets, pills, capsules, semisolids,powders, sustained release formulations, solutions, suspensions,emulsions, syrups, elixirs, aerosols, or any other appropriatecompositions; and comprise at least one compound of this invention,optionally in combination with at least one pharmaceutically acceptableexcipient. Suitable excipients are well known to persons of ordinaryskill in the art, and they, and the methods of formulating thecompositions, can be found in such standard references as Alfonso A R:Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton Pa., 1985, the disclosure of which is incorporated herein byreference in its entirety and for all purposes. Suitable liquidcarriers, especially for injectable solutions, include water, aqueoussaline solution, aqueous dextrose solution, and glycols.

The carbamate compounds can be provided as aqueous suspensions. Aqueoussuspensions of the invention can contain a carbamate compound inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients can include, for example, a suspendingagent, such as sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).

The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions for use in the present methods can be formulated bysuspending a carbamate compound in a vegetable oil, such as arachis oil,olive oil, sesame oil or coconut oil, or in a mineral oil such as liquidparaffin, or a mixture of these. The oil suspensions can contain athickening agent, such as beeswax, hard paraffin or cetyl alcohol.Sweetening agents can be added to provide a palatable oral preparation,such as glycerol, sorbitol or sucrose. These formulations can bepreserved by the addition of an antioxidant such as ascorbic acid. As anexample of an injectable oil vehicle, see Minto, J. Pharmacol. Exp.Ther. 281:93 (1997). The pharmaceutical formulations of the inventioncan also be in the form of oil-in-water emulsions. The oily phase can bea vegetable oil or a mineral oil, as described above, or a mixture ofthese.

Suitable emulsifying agents include naturally occurring gums, such asgum acacia and gum tragacanth, naturally occurring phosphatides, such assoybean lecithin, esters or partial esters derived from fatty acids andhexitol anhydrides, such as sorbitan mono-oleate, and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan mono-oleate. The emulsion can also containsweetening agents and flavoring agents, as in the formulation of syrupsand elixirs. Such formulations can also contain a demulcent, apreservative, or a coloring agent.

The compound of choice, alone or in combination with other suitablecomponents can be made into aerosol formulations (i.e., they can be“nebulized”) to be administered via inhalation. Aerosol formulations canbe placed into pressurized acceptable propellants, such asdichlorodifluoromethanc, propane, nitrogen, and the like.

Formulations of the present invention suitable for parenteraladministration, such as, for example, by intraarticular (in the joints),intravenous, intramuscular, intradermal, intraperitoneal, andsubcutaneous routes, can include aqueous and non-aqueous, isotonicsterile injection solutions, which can contain antioxidants, buffers,bacteriostats, and solutes that render the formulation isotonic with theblood of the intended recipient, and aqueous and non-aqueous sterilesuspensions that can include suspending agents, solubilizers, thickeningagents, stabilizers, and preservatives. Among the acceptable vehiclesand solvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter.

Where the compounds are sufficiently soluble they can be dissolveddirectly in normal saline with or without the use of suitable organicsolvents, such as propylene glycol or polyethylene glycol. Dispersionsof the finely divided compounds can be made-up in aqueous starch orsodium carboxymethyl cellulose solution, or in suitable oil, such asarachis oil. These formulations can be sterilized by conventional,well-known sterilization techniques. The formulations can containpharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike.

The concentration of a carbamate compound in these formulations can varywidely, and will be selected primarily based on fluid volumes,viscosities, body weight, and the like, in accordance with theparticular mode of administration selected and the patient's needs. ForIV administration, the formulation can be a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,such as a solution of 1,3-butanediol. The formulations of commends canbe presented in unit-dose or multi-dose sealed containers, such asampoules and vials. Injection solutions and suspensions can be preparedfrom sterile powders, granules, and tablets of the kind previouslydescribed.

A carbamate compound suitable for use in the practice of this inventioncan be administered orally. The amount of a compound of the presentinvention in the composition can vary widely depending on the type ofcomposition, size of a unit dosage, kind of excipients, and otherfactors well known to those of skill in the art. In general, the finalcomposition can comprise, for example, from 0.000001 percent by weight(% w) to 100% w of the carbamate compound, e.g., 0.00001% w to 50% w,with the remainder being the excipient or excipients.

Pharmaceutical formulations for oral administration can be formulatedusing pharmaceutically acceptable carriers well known in the art indosages suitable for oral administration. Such carriers enable thepharmaceutical formulations to be formulated in unit dosage forms astablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc. suitable for ingestion by thepatient. In other embodiments, pharmaceutical formulations for oraladministration can be formulated without using any pharmaceuticallyacceptable carriers.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of the pharmaceutical formulationsuspended in a diluents, such as water, saline or PEG 400; (b) capsules,sachets or tablets, each containing a predetermined amount of the activeingredient, as liquids, solids, granules or gelatin; (c) suspensions inan appropriate liquid; and (d) suitable emulsions.

Pharmaceutical preparations for oral use can be obtained throughcombination of the compounds of the present invention with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable additional compounds, ifdesired, to obtain tablets or dragee cores. Suitable solid excipientsare carbohydrate or protein fillers and include, but are not limited tosugars, including lactose, sucrose, mannitol, or sorbitol; starch fromcorn, wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxymethyl cellulose, hydroxypropylmethyl-cellulose orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen.

If desired, disintegrating or solubilizing agents can be added, such ascross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate. Tablet forms can include one or moreof lactose, sucrose, mannitol, sorbitol, calcium phosphates, cornstarch, potato starch, microcrystalline cellulose, gelatin, colloidalsilicon dioxide, talc, magnesium stearate, stearic acid, and otherexcipients, colorants, fillers, binders, diluents, buffering agents,moistening agents, preservatives, flavoring agents, dyes, disintegratingagents, and pharmaceutically compatible carriers. Lozenge forms cancomprise the active ingredient in a flavor, e.g., sucrose, as well aspastilles comprising the active ingredient in an inert base, such asgelatin and glycerin or sucrose and acacia emulsions, gels, and the likecontaining, in addition to the active ingredient, carriers known in theart.

The compounds of the present invention can also be administered in theform of suppositories for rectal administration of the drug. Theseformulations can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperatures and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

The compounds of the present invention can also be administered byintranasal, intraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187(1995); Tjwa, Ann. Allergy Asthma Immunol. 75:107 (1995)).

The compounds of the present invention can be delivered transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

Encapsulating materials can also be employed with the compounds of thepresent invention and the term “composition” can include the activeingredient in combination with an encapsulating material as aformulation, with or without other carriers. For example, the compoundsof the present invention can also be delivered as microspheres for slowrelease in the body. In one embodiment, microspheres can be administeredvia intradermal injection of drug (e.g., mifepristone)-containingmicrospheres, which slowly release subcutaneously (see Rao, J. Biomater.Sci. Polym. Ed. 7:623 (1995); as biodegradable and injectable gelformulations (see, e.g., Gao, Pharm. Res. 12:857 (1995)); or, asmicrospheres for oral administration (see, e.g., Eyles, J. Pharm.Pharmacol. 49:669 (1997)). Both transdermal and intradermal routesafford constant delivery for weeks or months. Cachets can also be usedin the delivery of the compounds of the present invention.

In another embodiment, the compounds of the present invention can bedelivered by the use of liposomes which fuse with the cellular membraneor are endocytosed, i.e., by employing ligands attached to the liposomethat bind to surface membrane protein receptors of the cell resulting inendocytosis. The active drug can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

By using liposomes, particularly where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecarbamate compound into target cells in vivo (see, e.g., Al-Muhammed, J.Microencapsul. 13:293 (1996); Chonn, Curr. Opin. Biotechnol. 6:698(1995); Ostro, Am. J. Hosp. Pharm. 46:1576 (1989)).

Active drug may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrug may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

In certain embodiments the compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories, for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation.

Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful, suppository andthe like, an amount of the active ingredient necessary to deliver aneffective dose as described above. For example, the pharmaceuticalcompositions herein can contain, per unit dosage unit, from about 10 toabout 1000 mg of the active ingredient, e.g., from about 25 to about 600mg of the active ingredient, e.g., from about 75 to about 400 mg of theactive ingredient, e.g., about 25, 50, 75, 100, 125, 150, 175, 200, 225,250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or600 mg or more or any range therein.

In some embodiments of the present invention, carbamate compoundssuitable for use in the practice of this invention will be administeredeither singly or concomitantly with at least one or more other compoundsor therapeutic agents, e.g., with other agents that treat obesity and/oraid in reduction of body weight or food intake. Examples of therapeuticagents for treating obesity and reducing of body weight or food intakeinclude, without limitation, leptin, leptin agonists, fenfluramine,dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y1 orY5 antagonists, cannabinoid CB 1 receptor antagonists or inverseagonists (e.g., rimonabant (ACOMPLIA), otenabant, ibinabant,surinabant), melanocortin receptor agonists, in particular,melanocortin-4 receptor agonists, ghrelin antagonists,melanin-concentrating hormone (MCH) receptor antagonists, CD38inhibitors, RP 105 inhibitors, MD-1 inhibitors, PYY(3-36) or PYY(3-36)agonists, amylin or amylin agonists, a CCK or CCK agonists, exendin orexendin agonists, a CNTF or CNTF agonists, serotonin reuptakeinhibitors, serotonin transport inhibitors, 5HT2c agonists, GLP-1 orGLP-1 agonists, DPP-IV inhibitors, opioid antagonists, orexinantagonists, metabotropic glutamate subtype 5 receptor antagonists,histamine 3 antagonist/inverse agonists, and topiramate.

In some embodiments, of the present invention, carbamate compoundssuitable for use in the practice of this invention will be administeredtogether with behavioral modifications, such as controlled diet and/orexercise.

The method includes the step of administering to a patient in need oftreatment or prevention an effective amount of one of the carbamatecompounds disclosed herein in combination with an effective amount ofone or more other compounds or therapeutic agents that have the abilityto provide advantageous combined effects such as the ability to augmentthe effects of the compounds of the invention.

Pharmaceutically acceptable salts and esters refers to salts and estersthat are pharmaceutically acceptable and have the desiredpharmacological properties. Such salts include salts that may be formedwhere acidic protons present in the compounds are capable of reactingwith inorganic or organic bases. Suitable inorganic salts include thoseformed with the alkali metals, e.g., sodium and potassium, magnesium,calcium, and aluminum. Suitable organic salts include those formed withorganic bases such as the amine bases, e.g., ethanolamine,diethanolamine, triethanolamine, tromethamine, N methylglucamine, andthe like. Pharmaceutically acceptable salts can also include acidaddition salts formed from the reaction of amine moieties in the parentcompound with inorganic acids (e.g., hydrochloric and hydrobromic acids)and organic acids (e.g., acetic acid, citric acid, maleic acid, and thealkane- and arene-sulfonic acids such as methanesulfonic acid andbenzenesulfonic acid). Pharmaceutically acceptable esters include estersformed from carboxy, sulfonyloxy, and phosphonoxy groups present in thecompounds. When there are two acidic groups present, a pharmaceuticallyacceptable salt or ester may be a mono-acid-mono-salt or ester or adi-salt or ester; and similarly where there are more than two acidicgroups present, some or all of such groups can be salified oresterified.

Compounds named in this invention can be present in unsalified orunesterified form, or in salified and/or esterified form, and the namingof such compounds is intended to include both the original (unsalifiedand unesterified) compound and its pharmaceutically acceptable salts andesters. The present invention includes pharmaceutically acceptable saltand ester forms of Formula I. More than one crystal form of anenantiomer of Formula I can exist and as such are also included in thepresent invention.

A pharmaceutical composition of the invention can optionally contain, inaddition to a carbamate compound, at least one other therapeutic agentuseful in the treatment of obesity and/or reduction in body weightand/or food intake. For example the carbamate compounds of Formula I canbe combined physically with other compounds in fixed dose combinationsto simplify their administration.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets.Second Edition. Revised and Expanded. Volumes 1-3, edited by Liebermanet al.; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: DisperseSystems. Volumes 1-2, edited by Lieberman et al.; published by MarcelDekker, Inc, the disclosure of each of which are herein incorporated byreference in their entireties and for all purposes.

The pharmaceutical compositions are generally formulated as sterile,substantially isotonic and in full compliance with all GoodManufacturing Practice (GMP) regulations of the U.S. Food and DrugAdministration.

The present invention provides methods of providing treatment orprevention of obesity and/or reduction in body weight and/or food intakein a subject using carbamate compounds. The amount of the carbamatecompound necessary to provide treatment or prevention of obesity isdefined as a therapeutically or a pharmaceutically effective dose. Thedosage schedule and amounts effective for this use, i.e., the dosing ordosage regimen will depend on a variety of factors including the stageof the disease, the patient's physical status, age and the like. Incalculating the dosage regimen for a patient, the mode of administrationis also taken into account.

A person of skill in the art will be able without undue experimentation,having regard to that skill and this disclosure, to determine atherapeutically effective amount of a particular substituted carbamatecompound for practice of this invention (see, e.g., Lieberman,Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The Art,Science and Technology of Pharmaceutical Compounding; and Pickar, 1999,Dosage Calculations). A therapeutically effective dose is also one inwhich any toxic or detrimental side effects of the active agent isoutweighed in clinical terms by therapeutically beneficial effects. Itis to be further noted that for each particular subject, specific dosageregimens should be evaluated and adjusted over time according to theindividual need and professional judgment of the person administering orsupervising the administration of the compounds.

For treatment purposes, the compositions or compounds disclosed hereincan be administered to the subject in a single bolus delivery, viacontinuous delivery over an extended time period, or in a repeatedadministration protocol (e.g., by an hourly, daily or weekly, repeatedadministration protocol). The pharmaceutical formulations of the presentinvention can be administered, for example, one or more times daily, 3times per week, or weekly. In one embodiment of the present invention,the pharmaceutical formulations of the present invention are orallyadministered once or twice daily.

In this context, a therapeutically effective dosage of the biologicallyactive agent(s) can include repeated doses within a prolonged treatmentregimen that will yield clinically significant results to providetreatment for cataplexy. Determination of effective dosages in thiscontext is typically based on animal model studies followed up by humanclinical trials and is guided by determining effective dosages andadministration protocols that significantly reduce the occurrence orseverity of targeted exposure symptoms or conditions in the subject.Suitable models in this regard include, for example, murine, rat,porcine, feline, non-human primate, and other accepted animal modelsubjects known in the art. Alternatively, effective dosages can bedetermined using in vitro models (e.g., immunologic and histopathologicassays).

Using such models, only ordinary calculations and adjustments aretypically required to determine an appropriate concentration and dose toadminister a therapeutically effective amount of the biologically activeagent(s) (e.g., amounts that are orally effective intranasallyeffective, transdermally effective, intravenously effective, orintramuscularly effective to elicit a desired response). The effectiveamount, however, may be varied depending upon the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

In an exemplary embodiment of the present invention, unit dosage formsof the compounds are prepared for standard administration regimens. Inthis way, the composition can be subdivided readily into smaller dosesat the physician's direction. For example, unit dosages can be made upin packeted powders, vials or ampoules and preferably in capsule ortablet form.

Effective administration of the carbamate compounds of this inventioncan be, for example, at an oral or parenteral dose of from about 0.01mg/kg/dose to about 150 mg/kg/dose. For example, administration can befrom about 0.1/mg/kg/dose to about 25 mg/kg/dose, e.g., from about 0.2to about 18 mg/kg/dose, e.g., from about 0.5 to about 10 mg/kg/dose.Therefore, the therapeutically effective amount of the active ingredientcan be, for example, from about 1 mg/day to about 7000 mg/day for asubject having, for example, an average weight of 70 kg, e.g., fromabout 10 to about 2000 mg/day, e.g., from about 50 to about 600 mg/day,e.g., about 10, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300,325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg/day ormore or any range therein. In one embodiment, the compound of Formula Iis administered in the form of a capsule at a dose of about 150 mg toabout 300 mg without any excipients.

The methods of this invention also provide for kits for use in providingtreatment or prevention of obesity and/or reduction in body weightand/or food intake. After a pharmaceutical composition comprising one ormore carbamate compounds of this invention, with the possible additionof one or more other compounds of therapeutic benefit, has beenformulated in a suitable carrier, it can be placed in an appropriatecontainer and labeled for providing treatment or prevention of obesityand/or reduction in body weight and/or food intake. Additionally,another pharmaceutical comprising at least one other therapeutic agentcan be placed in the container as well and labeled for treatment of theindicated disease. Such labeling can include, for example, instructionsconcerning the amount, frequency and method of administration of eachpharmaceutical.

Having described the present invention, the same will be explained ingreater detail in the following examples, which are included herein forillustration purposes only, and which are not intended to be limiting tothe invention.

Example 1 Effect of R228060 on Body Weight and Food Consumption in Rats

A 6-month repeated dose oral toxicity study with 3-month recovery wascarried out in rats for R228060 (Formula Ib). Body weight and foodconsumption were monitored throughout the study.

Body Weight

Body weight and weight gain of males dosed with R228060 at 35 mgHCl-salt/kg body weight/day was slightly lower compared to control rats,reaching statistical significance from week 8 to week 12 (body weightgain: p<0.05) and from week 10 to 12 (body weight: p<0.05). Body weightgain was decreased with 6% in week 13 and with 5% in week 26. Oraldosing with R228060 at 35 mg HCl-salt/kg body weight/day for 6consecutive months did not adversely affect body weight and body weightgain in female rats.

In males dosed at 300 mg HCl-salt/kg body weight/day, a pronounceddecrease in body weight and body weight gain from the first week ofdosing (p<0.001) was noted. Body weight gain was decreased with 27% inweek 13 and with 24% in week 26. In females at the same dose level, bodyweight gain showed a moderate to pronounced decrease (p<0.05-0.001),especially towards the end of the dosing period. Body weight gain was15% decreased compared to the control group in week 13, while a 23%decrease was noted in week 26. This resulted in a moderately decreasedbody weight (p<0.05-0.001).

Males dosed with R228060 at 600/450 mg HCl-salt/kg body weight/dayshowed a pronounced decrease in body weight and body weight gain fromweek 1 onwards (p<0.001). Body weight gain was decreased with 33% inweek 13, and with 32% in week 26. In females, a moderate to pronounceddecrease in body weight gain (p<0.05-0.001) was recorded from the firstweek of dosing. Body weight gain was decreased with 18% in week 13, andwith 21% in week 26. This resulted in a moderately decreased body weight(p<0.05-0.001). As evidenced by the increase in body weight gainstarting in the first week of recovery, male rats showed a partialregain of their normal (control) body weight after cessation oftreatment. At the end of the three month recovery period the body weightwas still moderately lower as compared to those of control animals.Similar findings were noted for females also resulting in a partialregain of their normal body weight. Compared to control animals theremaining body weight difference at the end of the recovery period wasonly slightly lower for the 600/450 mg HCl-salt/kg treated females.

In conclusion, body weights and body weight gains showed a dose-relateddecrease starting at 35 mg HCl-salt/kg body weight/day for males and 300mg HCl-salt/kg body weight/day for females. At the end of the treatmentperiod this resulted in decreases in body weight gain up to 32% and 21%for males and females respectively. After the 3-month recovery periodthe body weight losses were regained partially (males) to almostcompletely (females).

Food Consumption

Especially during the first weeks of dosing, for both sexes adose-related decrease in food consumption was noted starting at 35 mgHCl-salt/kg body weight/day for males and 300 mg HCl-salt/kg bodyweight/day for females. This resulted in statistically significantdecreases at the 300 and 600/450 mg HCl-salt/kg body weight level.Depending on the dose level, normal food consumption levels wereregained in time. For males at the 600/450 mg HCl-salt/kg body weightlevel food intake recovered to normal approximately 12 weeks afterinitiation of treatment. For females this occurred earlier, food intakerecovered to normal after about 4 weeks of treatment. In general, afterregaining normal food consumption levels, no relevant changes in foodintake were noted anymore. The noted statistically significant increasesin food consumption at the 35, 300 and 600/450 mg HCl-salt/kg bodyweight level in females were considered to be toxicologicallyirrelevant.

In conclusion, dose-related decreases in food consumption were noted inboth sexes especially in the first week(s) of dosing starting at 35 mgHCl-salt/kg body weight/day for males and 300 mg HCl-salt/kg bodyweight/day for females. At the 300 and 600/450 mg HCl-salt/kg bodyweight level, these decreases were statistically significant. Dependingon the dose level and gender, normal food consumption levels wereregained in time. Food consumption in males recovered later to normallevels as compared to females (respectively about 12 or 4 weeks afterinitiation of treatment).

Example 2 Effect of R228060 on Body Weight and Food Consumption in does

A 52-week repeated dose oral toxicity study with 13-week recovery wascarried out in beagle dogs for R228060 (Formula Ib). Body weight andfood consumption were monitored throughout the study (see Table 1).

Body Weight

Body weight losses were noted in all males treated at 25 or 50 mg/kgbw/day during the first 4 days of treatment, with a mean body weightloss of 0.3 kg and 0.7 kg, respectively. The mean body weight lossreached 0.8 kg on day 21 for the high dose male group and weights onlyreturned to the initial values on day 126, while males receiving 25mg/kg bw/day returned to initial weights on day 35.

Body weight loss was also noted in all treated females at 10, 25, or 50mg/kg bw/day during the first 4 days of treatment, with a mean bodyweight loss of 0.4 kg, 0.5 kg and 0.7 kg, respectively. The mean bodyweight loss reached 0.8 kg on day 21 for the high dose female group andreturned to the initial weight on day 77, while females receiving 10 or25 mg/kg bw/day returned to the initial weight on day 28 and 42,respectively.

A lower does-relative mean body weight gain was generally noted on days182 and 364 in treated groups, when compared to control.

Group 4 females had a higher body weight gain during the treatment-freeperiod while gains were only slightly higher in group 4 males, whencompared to controls.

TABLE 1 Group Day 4 Day 21 Day 182 Day 364 Day 455 Control males −1% +4%+32% +38% +52% (+2%) females −1% +1% +33% +47% +65% (+1%) 10 mg/kgbw/day males −1% 0% +22% +32% — females −6% −2% +26% +25% — 25 mg/kgbw/day males −4% −4% +71% +19% — females −7% −4% +16% +26% — 50 mg/kgbw/day males −9% −12% +7% +9% +12% (+6%) females −9% −12% +11% +9%  +26%(+26%) Values indicated in brackets represent the variation during thetreatment-free period only.Food Consumption

One male receiving 25 mg/kg bw/day had reduced food consumption (about−40%) during the first week of treatment, when compared to control.

Males receiving 50 mg/kg bw/day had a reduced food consumption (about−50% of the daily portion) mainly during the first week of treatment,one being more affected and still having lower food consumption untilday 42 as well as on several occasions at the end of the treatmentperiod.

Three out of four females receiving 10 mg/kg bw/day had a slightly lowerfood consumption (about −25% of the daily portion) during the first weekof treatment. Females receiving 25 mg/kg bw/day also had a lower foodconsumption (about −25 to −50% of the daily portion) during the firstweek of treatment. This was still noted on many occasions for twofemales throughout the treatment period. A lower food consumption, whichwas marked for 3/6 animals, was observed for all females receiving 50mg/kg bw/day during the first week of treatment. Thereafter, foodconsumption generally returned to normal values with only sporadicchanges during the rest of the treatment period. No effect on foodconsumption was noted for any animal during the treatment-free period.

Example 3 Effect of R228060 on Body Weight in Humans

A 6-week randomized, double blind, parallel group, active andplacebo-controlled study was carried out to assess the efficacy ofR228060 in adult subjects with major depressive disorder (MDD). Bodyweight was monitored throughout the study.

Table 2 summarizes the change in body weight from baseline to endpointby treatment group. Subjects who received R228060 experienced a meanweight loss of 0.6 kg in the 200-mg group and 0.9 kg in the 400-mggroup, while subjects who received placebo or paroxetine experiencedmean weight gains of 0.7 and 0.1 kg, respectively.

TABLE 2 Body Weight - Change from Baseline to Endpoint Placebo R228060200 mg R228060 400 mg Paroxetine Parameter: Weight (kg) (N = 121) (N =120) (N = 125) (N = 122) Baseline N 117 116 120 117 Mean (SD) 85.4(22.89) 86.0 (23.90) 84.1 (21.00) 83.1 (21.77) Median (Range) 82.1 (48;175) 84.4 (46; 147) 79.6 (44; 162) 79.8 (42; 154) End point N 117 116120 117 Mean (SD) 86.1 (22.99) 85.4 (24.03) 83.2 (21.20) 83.2 (22.06)Median (Range) 83.5 (48; 170) 83.4 (46; 148) 78.9 (44; 165) 79.8 (42;152) Change from Baseline N 117 116 120 117 Mean (SD)  0.7 (1.78) −0.6(1.90) −0.9 (2.20)  0.1 (1.92) Median (Range)  0.6 (−5; 8) −0.5 (−7; 5)−0.9 (−9; 5)  0.0 (−6; 7) SD = Standard deviation.

Table 3 shows the distribution of percent change in weight from baselineto endpoint by treatment group. Four subjects who received R228060 (1[0.9%] in the 200-mg group, 3 [2.5%] in the 400-mg group) had a decreasein weight of 7% or more. The percentage of subjects whose weight wasunchanged or decreased by less than 7% was greater in the R228060 groupsthan in the placebo or paroxetine groups. Correspondingly, thepercentage of subjects who had a weight gain of <7% weight was higher inthe placebo and paroxetine groups than in the R228060 groups.

TABLE 3 Body Weight - Distribution of Percent Change From Baseline toEndpoint R228060 R228060 Placebo 200 mg 400 mg Paroxetine Parameter (N =117) (N = 116) (N = 120) (N = 117) Character Value n (%) n (%) n (%) n(%) Weight classification 117 116 120 117 Decrease ≥7% 0 1 (0.9) 3 (2.5)0 No change/decrease <7% 40 (34.2) 75 (64.7) 90 (75.0) 62 (53.0)Increase <7% 74 (63.2) 39 (33.6) 27 (22.5) 54 (46.2) Increase ≥7% 3(2.6) 1 (0.9)  0 1 (0.9)

Mean changes from baseline to endpoint in BMI were small (−0.2 and −0.3kg/m² for R228060 200 mg and 400 mg, respectively, versus 0.2 kg/m² and0 for placebo and paroxetine, respectively).

All publications, patent applications, patents and other referencescited herein are incorporated by reference in their entireties for theteachings relevant to the sentence and/or paragraph in which thereference is presented and for any other purpose for which it can beused.

We claim:
 1. A method for reducing or preventing body weight gain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integer of 0 to 3, with the proviso that R may be the same or different when x is 2 or 3; R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a 5 to 7-membered heterocycle that is unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocycle can comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the oxygen atom; wherein the subject reduces body weight.
 2. The method of claim 1, wherein x=0.
 3. The method of claim 1, wherein R₁ and R₂ are hydrogen and x=0.
 4. The method of claim 1, wherein the compound of Formula I is an enantiomer of Formula I substantially free of other enantiomers or an enantiomeric mixture wherein one enantiomer of Formula I predominates.
 5. The method of claim 4, wherein the enantiomer of Formula I predominates to the extent of about 90% or greater.
 6. The method of claim 4, wherein the enantiomer of Formula I predominates to the extent of about 98% or greater.
 7. The method of claim 4, wherein the enantiomer of Formula I is an enantiomer of Formula Ia:

or a pharmaceutically acceptable salt or ester thereof.
 8. The method of claim 7, wherein the enantiomer of Formula Ia is the (R) or (D) enantiomer.
 9. The method of claim 7, wherein the enantiomer of Formula Ia is the (S) or (L) enantiomer.
 10. The method of claim 7, wherein the enantiomer of Formula Ia predominates to the extent of about 90% or greater.
 11. The method of claim 7, wherein the enantiomer of Formula Ia predominates to the extent of about 98% or greater.
 12. The method of claim 4, wherein the enantiomer of Formula I substantially free of other enantiomers is the compound of Formula Ib or an enantiomeric mixture wherein the compound of Formula Ib predominates:

or a pharmaceutically acceptable salt or ester thereof.
 13. The method of claim 12, wherein the compound of Formula Ib predominates to the extent of about 90% or greater.
 14. The method of claim 12, wherein the compound of Formula Ib predominates to the extent of about 98% or greater.
 15. The method of claim 1, wherein the effective amount of the compound of Formula I is from about 0.01 mg/kg/dose to about 150 mg/kg/dose.
 16. The method of claim 1, wherein the effective amount of the compound of Formula I is from about 1 mg/day to about 7000 mg/day.
 17. The method of claim 1, wherein the compound of Formula I is administered orally.
 18. The method of claim 1, wherein the compound of Formula I is administered in the form of a capsule or tablet.
 19. The method of claim 1, wherein the compound of Formula I is administered in the form of a capsule at a dose of about 10 mg to about 1000 mg without any excipients.
 20. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein R is a member selected from the group consisting of alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy of 1 to 3 carbon atoms; x is an integer of 0 to 3, with the proviso that R may be the same or different when x is 2 or 3; R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms; or R₁ and R₂ can be joined to form a 5 to 7-membered heterocycle that is unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocycle can comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the oxygen atom. 